Pauciarticular onset juvenile rheumatoid arthritis (pauci JRA) is the most common form of pediatric rheumatic disease, and accounts for significant morbidity from both musculoskeletal and ocular complications. The etiology is unknown. We and others have elucidated the striking HLA associations with this condition, which are unique and complex: HLA-DR8 and DR5 are strongly associated with disease, and DPB2.1 confers independent susceptibility, while other class II alleles such as DR4 appear to provide protection. Some evidence of limited T cell receptor usage is also emerging. The triggering antigen, however, remains a crucial factor in disease pathogenesis about which very little is known. Its elucidation may provide the most direct means of developing novel therapeutic or prevention strategies. We propose to utilize original molecular approaches to begin to identify the antigen(s) triggering pauci JRA in susceptible hosts. Specifically, we will derive peptide motifs which bind well to DR8 and DR5, but not to DR4, using molecular modeling and experimental peptide binding assays. We will utilize that motif to identify potential binding peptides from known sequences of candidate triggering antigens and test these directly for binding. As a complementary, independent approach, we will derive DR8 and DR5 binding peptides that are expressed in pauci JRA synovial samples, using a novel molecular expression approach. Finally, we will test these derived peptides directly for reactivity with patient synovial T cells. This project tackles a critical gap in our understanding of a poorly understood disease, and potentially will provide the basis for novel therapeutic or preventive strategies.